Primitive premature ejaculation is regarded as the most common sexual disorder of the male. This may cause a loss of the ability to achieve sexual accommodation which is necessary for the satisfaction of the human instinctive desire. Recently, it has been determined that the number of cases manifesting various symptoms caused by such loss of sexual accommodation is rather large. The sexual problems due to premature ejaculation in men lead to social difficulties, such as asthenia due to the loss of self-confidence, as well as domestic discord. Premature ejaculation is defined as persistent or recurrent ejaculation before, upon, or shortly after penetration
By nature, a woman is so evolved that she experiences the sex act markedly less intensely than a man, at least at the commencement of sexual activity. She must, therefore, have more time in order to reach the orgasm which provides natural relaxation of the whole nervous system strained to the maximum during the act. To this day the sense of touch plays an important role in human sex life; particularly sensitive to touch are the erogenous zones, first and foremost among them being the areas where skin borders on mucous membrane as, for example, in the vicinity of the oral cavity, the rectum, female genitals and breast nipples. The erogenous zone of a woman can be her entire body surface. In such cases it is possible to evoke lascivious feelings in her by touching any part of her body. But it is most often the case that erogenous zones are localized in strictly defined places such as: the clitoris, labia minora and the vagina. There are, additionally, many such sensitive points apart from the sex organs. These are: the lips, the ears, eyelids, neck, nipples, etc. In some cases these points are so sensitive that merely touching them can produce an orgasm in a woman.
However in the case of men, the erogenous zones are confined solely to the genitals and adjacent areas. It is not surprising, therefore, that an experienced male partner is sometimes obliged to undertake veritable journeys of exploration, in his search for these points, without which no one can activate the complex apparatus of female sexual reflexes. That is one reason the male often needs incomparably less time in order to reach orgasm—which usually concludes the sex act not only for himself but also for his partner. At the commencement of the sex act the man already finds himself at a certain level of excitement, which is essential to erection and without which this act becomes quite impossible. He is unable to continue the act out of consideration for his partner because immediately after orgasm and the associated ejaculation detumescence takes place and all further frictiones in vagina are impossible.
The ideal intercourse would be one in which, following immersing the penis into the vagina, both parties reached the boundary of orgasm simultaneously and, having crossed it, ended the sex act together (FIG. 1). This happens sometimes where a woman experienced in sexual intercourse can compensate for the excitement missing at the beginning of the act and reach the finishing line together with her partner in spite of that. For young and middle-aged men the norm of normal ejaculation vacillates between 2-6 minutes after the immersing the penis into the vagina.
The premature ejaculation occurs very frequently in the modern human sexual act. It concerns the fact that shortly after immersing the penis into the vagina takes place (FIG. 2), sometimes after 2-3 movements, ejaculation and orgasm occur; the erection vanishes and the sex act is ended. Obviously in such a situation the woman is only aroused, while there can be no question of release. Obviously there can be no question of sexual satisfaction and normal relaxation of the female partner in the presence of any kind of male impotence, whether through inadequate erection or through premature ejaculation.
Erection of the penis may be a self-perpetuating process of three steps: 1) vasodilation; 2) release of endogenous smooth-muscle relaxants; and, 3) progression of these effects distal from the initial site of onset. This has been termed the “cascade effect”. Papaverine is an opium alkaloid and works as a smooth muscle relaxer possibly by cyclic GMP phosphodiesterase inhibition. It relaxes the musculature of the vascular system of the penis and increases blood flow (Papaverine Topical Gel Treatment For Erectile Dysfunction, Urology, Vol. 133(2)(1995), pp. 361-365). Another compound found useful in the treatment of impotence is prostaglandin E1, a naturally occurring compound that acts to increase arterial inflow to the penis and may also restrict venous outflow. Prostaglandin E1 is preferred to other compounds used in injections for the treatment of impotence because it is metabolized locally in the penis and is less likely to cause systemic symptoms such as hypotension. As a modified vascular tissue, corpora carvernosa of the penis (ccp) produces and secretes the same range of autocrine and paracrine regulators as conventional vascular tissue. The smooth muscle tone of the ccp, however, does not appear to be regulated in the same manner as in the vascular wall. Presently it is postulated that the tone or contractility of ccp is modulated by adrenergic regulation and locally produced NO and endothelin. In the ccp, most studies have been directed to observing the relaxing effects of NO, vasoactive intestinal peptide (VIP), calcitonin gene-related peptide (CGRP) and parasympathetic innervation, which also have similar effects on conventional and ccp vascular smooth muscle.
During normal penile erections, when the inflow of blood to the ccp engages the sinusoidal spaces, the trabecular tissue compresses small carvernosal veins against the thick fibrous tissue surrounding the corpora to maintain the erection. To mediate these changes in blood flow, nitric oxide is released from postsynaptic parasympathetic neurons and, to a lesser extent, endothelial cells and α-adrenergic neurons are inhibited in the arterial and trabecular smooth muscle. Nitric oxide, which is readily diffusible, stimulates the formation of increased cyclic guanosine monophosphate (GMP) in the corpus carvernosum by guanylate cyclase to relax the smooth muscle cells.
Recently, the oral use of the citrate salt of sildenafil has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of male erectile dysfunction. Sildenafil is reported to be a selective inhibitor of cyclic-GMP-specific phosphodiesterase type 5 (PDE5), the predominant isozyme metabolizing cyclic GMP formed in the corpus carvernosum. Since sildenafil is a potent inhibitor of PDE5 in the corpus carvernosum, it is believed to enhance the effect of nitric oxide, thereby increasing carvernosal blood flow in the penis, especially with sexual stimulation. Inasmuch as sildenafil at the currently recommended doses of 25-100 mg has little effect in the absence of sexual stimulation, sildenafil is believed to restore the natural erectile response to sexual stimulation but not cause erections in the absence of such stimulation (Goldstein 1998). The localized mechanism by which cyclic GMP stimulates relaxation of the smooth muscles has not been elucidated.
Normal ejaculatory function in the human male implies a coordinated sequence of smooth and striate muscular contractions to promote projectile, antegrade transport of seminal fluid. This process begins with transmission of afferent nerve stimuli via the internal pudendal nerve from the penile shaft to higher centers. To complete the ejaculatory reflex efferent stimuli are transmitted from the anterolateral columns of the spinal cord and emerging from the thoracolumbar level to comprise a hypogastric or sympathetic plexus. From the interior mesenteric ganglion short adrenergic postganglionic fibers terminate in the seminal vesicles, vasal ampullae, and bladder neck. Sympathetic innervation of the seminal vesicles results in seminal emission into the posterior urethra. Appropriately timed bladder neck closure prevents retrograde passage of this semen bolus, which is propelled in the antegrade direction by clonic contracts of the bulbocarvernosus and ischiocarvernosus muscles of the pelvic floor. Ejaculation is a centrally, integrated peripheral evoked reflex, which occurs as a result of α1-adrenergic receptor activation. Effective pharmacological drugs for the treatment of premature ejaculation exist, but they suffer from severe side effects, for example clomipramine and phenoxybenzamine. Other treatments have a limited effectiveness (metoclopramide and the like).
PGE2, PGF2α, PGF2β, PGA2, and PGB2, and their esters and pharmacologically acceptable salts, are extemely potent in causing various biological responses. For that reason, these compounds are useful for pharmacological purposes. See, for example, Bergstrom et al., Pharmacol. Rev. 20, 1 (168), and references cited therein. A few of those biological responses are systemic arterial blood pressure lowering in the case of PGE2, PGF2β, and PGA2 as measured, for example, in anesthetized (pentobarbital sodium) pentolinium-treated rats with indwelling aortic and right heart cannulas; pressor activity, similarly measured, for PGF2α; stimulation of smooth muscle as shown, for example, by tests on strips of guinea pig ileum, rabbit duodenum, or gerbil colon; potentiation of other smooth muscle stimulants; antilipolytic activity as shown by antagonism of epinephrine-induced mobilization of free fatty acids or inhibition of the spontaneous release of glycerol from isolated rat fat pads; inhibition of gastric secretion in the case of PGE2 and PGA2 as shown in dogs with secretion stimulated by food or histamine infusion; activity on the central nervous system; decrease of blood platelet adhesiveness as shown by platelet-to-glass adhesiveness, and inhibition of blood platelet aggregation and thrombus formation induced by various physical stimuli, e.g., arterial injury, and various biochemical stimuli, e.g., ADP, ATP, serotonin, thrombin, and collagen; and in the case of PGE2 and PGB2, stimulation of epidermal proliferation and keratinization as shown when applied in culture to embryonic chick and rat skin segments. PGE2 is extremely potent in causing stimulation of smooth muscle, and is also highly active in potentiating other known smooth muscle stimulators, for example, oxytocic agents, e.g., oxytocin, and the various ergot alkaloids including derivatives and analogs thereof. Therefore PGE2 is useful in place of or in combination with less than usual amounts of these known smooth muscle stimulators, for example, to relieve the symptoms of paralytic ileus, to control or prevent atonic uterine bleeding after abortion or delivery, to aid in expulsion of the placenta, and during the puerperium.
A synthetic form of prostaglandin E1, alprostadil USP (alprostadil), is a long-chain carboxylic acid with vasodilatory effects. Alprostadil acts to increase arterial inflow to the penis. In vitro studies have shown that alprostadil causes a dose-dependent smooth muscle relaxation in isolated corpus carvernosum and corpus spongiosum preparations. When used in vivo, it is thought that intraurethral alprostadil is absorbed from the urethra, transported throughout the erectile bodies of the penis by way of communicating vessels between the corpus spongiosum and corpus carvernosum, and induces vasodilation of the targeted vascular beds. U.S. Pat. No. 5,658,936 teaches that similar to the vascular tissue, the corpus carvernosum penis produces and secretes angiotensin II, that plays an important role in modulation of the penile blood flow. Local, intracarvernosal, or systemic administration of angiotensin II antagonists or ACE inhibitors has a powerful effect on the penile blood flow. (U.S. Pat. No. 5,658,936: Enhancement of erectile function with renin-angiotensin system inhibitors)
Dextromethorphan (frequently abbreviated as DM) is the common name for(+)-3-methoxy-N-methylmorphinan (FIG. 3). It widely used as a cough syrup, and is described in references such as Rodd 1960 (full citations to articles are provided below) and Goodman and Gilman's Pharmacological Basis of Therapeutics. Briefly, DM is a non-addictive opioid comprising a dextrorotatory enantiomer (mirror image) of the morphinan ring structure which forms the molecular core of most opiates. DM acts at a class of neuronal receptors known as sigma receptors. These are often referred to as sigma opiate receptors, but there is some question as to whether they are opiate receptors, so many researchers refer to them simply as sigma receptors, or as high-affinity dextromethorphan receptors. They are inhibitory receptors, which means that their activation by DM or other sigma agonists causes the suppression of certain types of nerve signals. Dextromethorphan also acts at another class of receptors known as N-methyl-D-aspartate (NMDA) receptors, which are one type of excitatory amino acid (EAA) receptor. Unlike its agonist activity at sigma receptors, DM acts as an antagonist at NMDA receptors, which means that DM suppresses the transmission of nerve impulses mediated via NMDA receptors. Since NMDA receptors are excitatory receptors, the activity of DM as an NMDA antagonist also leads to the suppression of certain types of nerve signals, which may also be involved in some types of coughing. Due to its activity as an NMDA antagonist, DM and one of its metabolites, dextrorphan, are being actively evaluated as possible treatments for certain types of excitotoxic brain damage caused by ischemia (low blood flow) and hypoxia (inadequate oxygen supply), which are caused by events such as stroke, cardiac arrest, and asphyxia. The anti-excitotoxic activity of dextromethorphan and dextrorphan, and the blockade of NMDA receptors by these drugs, are discussed in items such as Choi 1987, Wong et al 1988, Steinberg et al 1988, and U.S. Pat. No. 4,806,543 (Choi 1989). Dextromethorphan has also been reported to suppress activity at neuronpal calcium channels (Carpenter et al 1988). Dextromethorphan and the receptors it interacts with are further discussed in Tortella et al 1989, Leander 1989, Koyuncuoglu & Saydam 1990, Ferkany et al 1988, George et al 1988, Prince & Feeser 1988, Feeser et al 1988, Craviso and Musacchio 1983, and Musacchio et al 1988.
DM disappears fairly rapidly from the bloodstream (see, e.g., Vetticaden et al 1989 and Ramachander et al 1977). DM is converted in the liver to two metabolites called dextrorphan and 3-methoxymorphinan, by an enzymatic process called O-demethylation; in this process, one of the two pendant methyl groups is replaced by hydrogen. If the second methyl group is removed, the resulting metabolite is called 5-hydroxymorphinan. Dextrorphan and 5-hydroxymorphinan are covalently bonded to other compounds in the liver (primarily glucuronic acid or sulfur-containing compounds such as glutathione) to form glucuronide or sulfate conjugates which are eliminated fairly quickly from the body via urine bloodstream. This enzyme is usually referred to as debrisoquin hydroxylase, since it was discovered a number of years ago to carry out a hydroxylation reaction on debrisoquin. It is also referred to in various articles as P450 DB or P450-2D6. It apparently is identical to an enzyme called sparteine monooxygenase, which was shown years ago to metabolize sparteine; it was not until recently that scientists realized that a single isozyme appears to be primarily responsible for oxidizing both debrisoquin and sparteine, as well as dextromethorphan and various other substrates. Debrisoquin hydroxylase belongs to a family of enzymes known as “cytochrome P-450” enzymes, or as “cytochrome oxidase” enzymes. Monooxygenation of chemical materials has been ascribed to cytochromes P450 (P450). These hemoprotein containing monooxygenase enzymes displaying a reduced carbon monoxide absorption spectrum maximum near 450 nm have been shown to catalyze a variety of oxidation reactions including hydroxylation of endogenous and exogenous compounds (Jachau, 1990). An extensive amount of research has been conducted on the mechanism's by which P450's can catalyze oxygen transfer reactions (Testa and Jenner, 1981; Guengerich, 1992; Brosen et al, 1990; Murray et al, 1990; and Porter et al, 1991).
The P450 reaction cycle proceeds briefly as follows: initial binding of a substrate molecule (RH) to the ferric form of the cytochrome results in the formation of a binary complex and a shift in the spin equilibrium of the ferric enzyme from the low- to high-spin state. Some evidence has been presented that suggests this configuration more readily accepts an electron from the flavoprotein reductase to form the ferrous P450-substrate complex. However, not all P450s exhibit a relationship between high-spin content and reduction rate. Indeed, it has been proposed that several factors, including the nature of the P450 substrate, the topography of the enzyme/substrate complex, and the potentials of oxidizable atoms each play a role in regulation of the reduction rate. Molecular oxygen binds to the ferrous P450-substrate complex to form the ferrous dioxygen complex which is then reduced by a second electron from the P450 reductase (or perhaps, in some cases, from reduced nicotinamide adenine dinucleotide via cytochrome b5 and its reductase). Dioxygen bond cleavage in the reduced ferrous dioxygen complex results in the insertion of one atom of oxygen into the substrate, reduction of the other oxygen atom to water, and restoration of the ferric hemoprotein.
Individual members of the P450 family of enzymes and associated mixed function oxidase activities have been described in extrahepatic tissues including brain, adrenal, kidney, testis, ovary, lung and skin. Individual P450s have likewise been characterized in terms of their inducibility by selected chemical classes. Induction of specific P450 enzymes, such as the P450 1A1 and 1A2 subfamily have been extensively studied with respect to regulatory processes of increased mRNA transcription and expression of enzymatic activity. It has been ascertained that materials such as beta-naphthaflavone (beta-NF), 3-methylcholanthrene (3-MC), arochlor 1254 (ACLR) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) are materials that have been categorized as inducers of P450 enzymes bearing the designated P450 1A subfamily (Murray et al, 1990; and Guengerich, 1989).
A number of compounds inhibit the activity of the debrisoquin hydroxylase (sparteine monooxygenase) isozyme (Inaba et al 1985). The most powerful of these inhibitors is quinidine (FIG. 3), a dextrorotatory stereoisomer of quinine; it is normally used to treat cardiac arrhythmias. Inaba et al (1986) and Nielsen et al (1990) discuss the ability of quinidine to inhibit the oxidation of sparteine in in vivo animal tests, and Brinn et al (1986), Brosen et al (1987), and Broly et al (1989) discuss the ability of quinidine to inhibit DM metabolism in liver cell preparations. In addition to the inhibition of debrisoquin hydroxylase, which is exceptionally potent and easily demonstrated, other cytochrome P450 isozymes are also likely to be suppressed by quinidine, with varying levels of binding affinity. Accordingly, even though quinidine exerts its most marked effect on debrisoquin hydroxylase, it is likely to suppress a number of other cytochrome P450 enzymes as well, thereby subjecting a patient to a more general loss of normal and desirable liver activity. The primary oxidized metabolic product of dextromethorphan is dextrorphan, which is widely believed among neurologists to be active in exactly the same manner as dextromethorphan; both drugs reportedly are sigma agonists, NMDA antagonists, and calcium channel antagonists. It has been shown that the administration of a compound which inhibits debrisoquin hydroxylase, in conjunction with DM, causes a major increase in the concentration and stability of DM in the blood of patients, compared to patients who receive only DM; and the administration of a debrisoquin hydroxylase inhibitor in conjunction with DM has a clear and substantial impact on the detectable effects of DM in humans.
Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used for treating common inflammation. NSAIDs mainly inhibit the synthesis of prostaglandins in the human body by inhibiting the enzyme cyclo-oxygenase(COX) which is essential for the synthesis of prostaglandins. The enzyme COX has two isomers called COX-1 and COX-2. COX also known as prostaglandin H synthase, is an enzyme implicated in the mediation of pain, fever, and inflammation. It catalyzes the oxidative conversion of arachidonic acid into prostaglandin H2, a key intermediate in the biosynthetic pathway of prostaglandins, prostacyclins, and thromboxanes, which in turn mediate a variety of physiological effects both beneficial and pathological. Recently, it was discovered that two COX isoforms exists: COX-1, expressed constitutively in many tissues, and COX-2, an induced isoform having elevated expression in inflamed tissues. COX-1 is thought to be involved in ongoing housekeeping functions, for example gastric cytoprotection, while COX-2 is the isoform implicated in the pathological effects mentioned above. Nonsteroidal anti-inflammatory agents (NSAIDs) such as aspirin, ibuprofen and indomethacin inhibit both COX-1 and COX-2. COX-2 inhibitors, celecoxib (Celebrex) and rofecoxib (Vioxx), are recently introduced prescription NSAIDs for osteoarthritis. Unlike previously available NSAIDs, which inhibit cyclooxygenase-1 (COX-1) and COX-2, celecoxib and rofecoxib specifically (about 350 fold) inhibit cyclooxygenase-2 (COX-2). Both actions are beneficial in blocking production of prostaglandins. However, inhibition of COX-1 is responsible for some side effects of older NSAIDs, such as upper gastrointestinal irritations and inhibition of platelet aggregation. Because celecoxib and rofecoxib specifically target COX-2, they do not affect platelet aggregation and are less likely to produce stomach and upper intestinal irritations.
At present, the treatment of choice for premature ejaculation is psychotherapy, either as a behavioural dual team sex therapy according to Master & Johnson protocol, or individual psychotherapy (Rifelli and Moro. Sessuologia Clinica. Bologna, 1989). Previous methods of treating premature ejaculation include psychological therapies, topical anesthetics and the use of devices (U.S. Pat. Nos. 5,535,758, 5,063,915, 5,327,910, and 5,468,212). All of these methods may have significant drawbacks. Psychological therapies benefit only a subset of patients and require specialized therapists who may not be available to all patients, particularly in remote areas. Furthermore, psychological therapies cannot alleviate premature ejaculation resulting from non-psychological causes. Anesthetic agents decrease sensitivity of tissues, thereby diminishing sexual pleasure. Also, topical anesthetics can be transferred to sexual partners and thereby decrease their sensitivity and pleasure as well. With regard to devices, these can be awkward, inconvenient and embarrassing to use. Devices are highly conspicuous, and reveal the very condition which the suffering partner may prefer to conceal. Additionally, devices can cause irritation to one or both partners.
Methods for treating premature ejaculation by systemic administration of several different antidepressant compounds have been described (U.S. Pat. Nos. 4,507,323, 4,940,731, 5,151,448, and 5,276,042; PCT Publication No. WO95/13072). However, these drugs may not be effective for all patients, and the side effects of these drugs can halt treatment or impair patient compliance. Disease states or adverse interactions with other drugs may contraindicate the use of these compounds or require lower dosages that may not be effective to delay the onset of ejaculation. Additionally, the stigma of mental illness associated with antidepressant therapy can discourage patients from beginning or continuing such treatments. Administration of the antidepressant fluoxetine has been claimed to treat premature ejaculation (U.S. Pat. No. 5,151,448). However, the administration of fluoxetine may have many undesired aspects. Patients with hepatic or renal impairments may not be able to use fluoxetine due to its metabolism in the liver and excretion via the kidney. Systemic events during fluoxetine treatment involving the lungs, kidneys or liver have occurred, and death has occurred from overdoses. In addition, side effects of oral fluoxetine administration include hair loss, nausea, vomiting, dyspepsia, diarrhea, anorexia, anxiety, nervousness, insomnia, drowsiness, fatigue, headache, tremor, dizziness, convulsions, sweating, pruritis, and skin rashes. Fluoxetine interacts with a range of drugs, often by impairing their metabolism by the liver.
U.S. Pat. No. 4,940,731 describes the oral or parenteral administration of sertraline for treating premature ejaculation. It has been recognized that sertraline shares many of the same problems as fluoxetine; (see Martindale, The Extra Pharmacopoeia, 31 st edition, at p. 333 (London: The Royal Pharmaceutical Society, 1996)). Sertraline is metabolized in the liver, and is excreted in the urine and feces. Thus, patients with cirrhosis must take lower doses, and caution must be exercised when administering sertraline to patients with renal impairment. Individuals taking monoamine oxidase inhibitors cannot take sertraline due to the risk of toxicity, leading to memory changes, confusion, irritability, chills, pyrexia and muscle rigidity. Side effects resulting from oral sertraline administration include nausea, diarrhea, dyspepsia, insomnia, somnolence, sweating, dry mouth, tremor and mania. Rare instances of coma, convulsions, fecal incontinence and gynecomastia have occurred in patients undergoing sertraline therapy. U.S. Pat. No. 5,276,042 describes the administration of paroxetine for the treatment of premature ejaculation. Paroxetine is predominantly excreted in the urine, and decreased doses are recommended in patients with hepatic and renal impairments. Like sertraline, paroxetine cannot be given to patients undergoing treatment with a monoamine oxidase inhibitor. Side effects from oral administration of paroxetine include hyponatremia, asthenia, sweating, nausea, decreased appetite, oropharynx disorder, somnolence, dizziness, insomnia, tremor, anxiety, impaired micturition, weakness and paresthesia. Thus there is a need for a method of treating premature ejaculation that requires no specialized psychological therapy, can be used conveniently and without embarrassment, and does not involve the problems associated with prior therapeutic methods.
U.S. Pat. No. 6,037,360 discloses that administration of various serotonin agonists and antagonists is effective in the treatment of premature ejaculation. The adverse effects occurring most frequently during treatment with serotonin inhibitors are gastrointestinal disturbances, such as, for example nausea, diarrhea/loose stools, constipation. (Drugs 43 (Suppl. 2), 1992). Nausea is the main adverse effect in terms of incidence. Moreover it has been frequently observed that after administration of serotonin inhibitors, patients suffer from dyspepsia.
U.S. Pat. No. 5,707,999 teaches that two specific α1-blockers, alfuzosine and terazosine, are effective in the treatment of psychogenic premature ejaculation and said drugs turned out to be effective in patients who proved to have no benefit from psychological therapy. However terazosine and its analogs have several side effects including headache, nausea, weight gain, dizziness, somnolence, dyspnea and blurred vision.